Behavioural evaluation of candidate genetic, environmental and developmental murine models for preclinical schizophrenia research

Valid mouse models of schizophrenia (SCZ) are valuable preclinical research tools to investigate pathogenetic mechanisms and possible treatment strategies for this devastating and poorly understood brain disease. The purpose of current PhD project was to develop and/or evaluate three such models in an extensive test battery that screened for schizophreniform behaviour. The three models focussed on different neurogenetic and environmental factors that have been implicated in SCZ pathogenesis. The first model is a mouse line with haploinsufficiency of the vesicular glutamate transporter 2 (VGLUT2). Behavioural changes of VGLUT2 haploinsufficient mice included hypersensitivity to amphetamine (indirect dopamine agonist) and MK-801 (non-competitive NMDA-receptor antagonist). The second model comprised post-weaning social isolation (isolation rearing) as an environmental manipulation. Such socially isolated mice displayed spontaneous and amphetamine-induced hyperactivity, alterations in prepulse inhibition and habituation of the startle reflex, alterations in social behaviour and impaired extinction of cued fear and spatial memory. In addition, specific brain areas known to be involved in SCZ symptomatology (prefrontal cortex and ventral striatum) showed alterations in gene expression of elements involved in dopamine transmission (dopamine receptor D1 and vesicular monoamine transporter 2). The third model focussed on neurodevelopmental processes involved in SCZ. Lesioning of the ventral hippocampus at neonatal age is known to result in a variety of SCZ-related behaviours in rats, but was here for the first time applied in mice. After anaesthetic procedures as well as lesion coordinates were established in preliminary experiments, behavioural characterization of these mice suggested hyperactivity and alterations in working memory, although large lesion variability comtinued to complicate study results. Experimental results of the three mouse models are discussed in relation to validity of these models as well as their significance in the identification of pathogenetic mechanisms.status: publishe

Emotional disorders in adult mice heterozygous for the transcription factor Phox2b

Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development.publisher: Elsevier articletitle: Emotional disorders in adult mice heterozygous for the transcription factor Phox2b journaltitle: Physiology & Behavior articlelink: http://dx.doi.org/10.1016/j.physbeh.2015.01.012 content_type: article copyright: Copyright © 2015 Elsevier Inc. All rights reserved.status: publishe

Behavioural alterations relevant to developmental brain disorders in mice with neonatally induced ventral hippocampal lesions

Neonatal lesioning of the ventral hippocampus (vHc) in rats has served as a useful heuristic animal model to elucidate neurodevelopmental mechanisms of schizophrenia (SCZ). In the current study we have established that this procedure can be applied to model SCZ symptomatology in mice. Neonatal mice (postnatal day 6) were anaesthetised by hypothermia and electrolytic lesions of the vHc were induced. We observed locomotor hyperactivity at prepubertal and adult age and hypersensitivity to amphetamine. Furthermore, working memory deficits were observed in Y-maze (spontaneous alternation) and T-maze (exploration of a novel arm) test protocols. Decreased anxious behaviour in the elevated plus maze and increased sociability were also observed. These changes were dependent on lesion size. No differences were observed in prepulse inhibition of the startle reflex, latent inhibition, spatial memory (Morris water maze), problem solving capacities (syringe puzzle) and ability to discriminate between different unfamiliar mice. The presented findings might further help to identify neurobiological mechanisms of neurodevelopmental disorders.status: publishe

Serotonin transporter binding in the hypothalamus correlates negatively with tonic heat pain ratings in healthy subjects: A [11C]DASB PET study

status: publishe